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Regulators grapple with Canada’s first generic biologic drug

Biologic drugs have revolutionized treatments for diseases from cancer to multiple sclerosis. But because they’re developed out of living organisms, they’re more expensive than conventional drugs, adding to the strain on publicly funded drug plans.

Fortunately, a new shift should make them cheaper. Many biologics will soon have their patents expire. That means Subsequent Entry Biologics (SEB) – which are similar to generic drugs, and called biosimilars in other countries – are about to enter the Canadian market. These SEBs offer the chance to save money, but questions have been raised about their safety, leaving policy makers with tough decisions.

The first SEB that will compete with a biologic drug is Inflectra, an SEB of Remicade, a common treatment for arthritis, psoriasis and Crohn’s disease. On December 23, Inflectra received a positive recommendation from the Common Drug Review. The recommendation notes that it’s about a third cheaper, at $650 per 100 mg vial versus Remicade’s $987.56 per 100 mg.

“Any day now, the provinces will turn their attention to listing [Inflectra] on their formularies, and from there, patients and physicians will start their first interaction with a biosimilar,” says Kim Furlong, director of federal government affairs and policy at Amgen, a company that makes biologics.

More will inevitably follow. Another half a dozen biologics’ patents have expired in the past few years, and the number of biosimilars is rising around the world. “The pipeline for SEBs is huge,” says Chander Sehgal, director of the CADTH Common Drug Review. “We are anticipating receiving one to three submissions per year over the next few years.”

In response to this rise, the Canadian Society of Nephrology recently released three papers covering the efficacy and safety of SEBs, potential cost savings, and their general impact on the field late last year. “We feel there are going to be SEBs in nephrology in 2015,” says Dan Martinusen, an author of the paper about cost and lead author of a report on the issue for the society. “These are not as simple to introduce as generic drugs, and I hope there’s good debate as to where they will fit.”

‘The process is the product’

Unlike regular drugs, which are made from small molecules, biologics are developed from living organisms, including animals, genes and microorganisms. They’re also complex molecules, and they can change in unpredictable ways during manufacturing – so much so that “the process is the product” is often used to describe them. Take Eprex, a well-tested biologic for anemia in kidney disease. A small change in its production methods – a switch to uncoated rubber syringe stoppers – led to some patients getting pure red cell aplasia, which causes severe anemia.

Less dramatic differences are known as “drift” – small changes that happen because of minor differences in the manufacturing process. Some use this phenomenon as an argument in favour of SEBs. But because SEBs must start from scratch when it comes to materials, equipment and processes, they have a larger chance of a significant shift than the original biologics do from batch to batch.

Like their generic counterparts, SEBs, which are approved by Health Canada on a drug-by-drug basis, require less proof of safety and efficacy than new biologics. To judge them, Health Canada compares the SEB to the previously approved biologic and looks at non-clinical studies; clinical trials aren’t as important as they are for new drugs. That’s because SEBs are deemed similar enough to the original biologic for some of the information to be transferable.

But despite the truncated process, an SEB isn’t just seen as a replica of the biologic. Generic drugs are judged on whether they’re bioequivalent, which means they contain the same amounts of the same active ingredient, which is absorbed by the body in the same way – and that they produce the same effect. But the complexity of biologics makes equivalency harder to establish. For example, Health Canada approved Inflectra for rheumatoid arthritis and psoriasis, but not for Crohn’s disease and ulcerative colitis, which Remicade is approved for, due to concerns that the differences between the two drugs could affect the SEB’s effectiveness and safety for those two conditions.

“The entry of SEBs into the Canadian market will ensure Canadians have access to alternative biological products. However, Health Canada’s activities and decisions related to SEBs will always have patient safety at the forefront,” Health Canada spokesperson Michael Valerio said.

Safety concerns around switching

This inherent unpredictability has raised questions about the safety of SEBs. Most agree people who are biologically naive – who have never been on a biosimilar before – could start with an SEB with few risks, in the same way that they might try other drugs before a biologic.

But there’s significant debate over the idea of interchangability, where people who are already on biologics would be switched to SEBs. That’s how many generic drugs are handled, with pharamacists making substitutions more or less automatically. That has led to significant savings, with generics making up nearly 63% of prescriptions but only 25% of the cost of prescriptions.

Health Canada doesn’t support automatically substituting SEBs for brand-name biologics. But the provinces are the ones who make decisions around substitution, and it’s too early to know what they’ll do. “I think all stakeholders are looking forward to seeing what type of policies jurisdictions will put in place [around interchangeability],” says Sehgal. Alberta is the only province so far that has taken a stance against substitution or interchangeability with SEBs.

Braden Manns, president of the Canadian Society of Nephrology, thinks governments will most likely add SEBs onto their plans while continuing to cover biologics for those already on them. That means patients wouldn’t be forced to switch. That’s Manns’ preference as well. “The only thing I think is clear is that these things aren’t interchangeable,” he says, adding “In the end, the only people that stand to win are the government if the price cuts are deep enough. All of these really don’t provide that much benefit to patients.”

Potential safety issues include the SEBs being stronger or weaker than their biosimilars. There’s also the possibility of accidentally triggering an immune response. Those concerns could be mitigated by doctors being educated about these potential issues and monitoring any patients who are switched to a SEB – which would mean pharmacists couldn’t switch patients to an SEB without informing their doctor.

In one of the few studies on the safety of substitution, a review of post-marketing and clinical data looked at 58 clinical trials, which involved 12,000 patients on erythropoietin, filgrastim and growth hormones. It concluded that “Although there may be valid reasons to be prudent with switching between biopharmaceuticals, including traceability of adverse events or concerns about patient anxiety, thus far there is no evidence that the process of switching in itself poses a risk to patients.”

Steve Morgan, director of the Centre for Health Services and Policy Research at UBC, is skeptical about the weight of these potential problems. “The dialogues around biosimilars sounds very familiar to the dialogue around generics in the 1970s,” he says. While it’s too early to declare SEBs and biologics interchangeable, “the safety concerns are manageable,” he says. “And – with due caution – it’s so important that we figure this out.”

The $900 million question

Biologics are expensive drugs, making up 14% of drug spending in Canada, at a cost of $3 billion a year. Remicade, for example, cost Ontario $84 million in 2012/13, or 4.3% of the Ontario Drug Benefit Plan’s drug budget. In the U.S., biologics cost about 20 times more than regular drugs, with some costing $100,000 a year.

SEBs could offer significant savings: in Europe, where they’ve been on the market since 2006, they’re 20% to 30% cheaper than biologics. And they create pressure for biologics to lower their effective prices. In Germany, where SEBs are more common, the costs of brand name biologics have come down. “The cost difference between the SEB and the innovator in Germany is now some of the smallest across Europe,” says Martinusen.

Nicole Tsao led a paper for the Canadian Society of Nephrology that looked at costs. It found switching to an epoetin SEB, which is used for anemia, could save $35 to $50 million a year in Canada. Those savings are crucial, says Morgan. “It is fundamental to the bargain that we make with industry that we get competition after the patents expire.”

But provinces are in a difficult position. “They need to be prudent managers of the funds,” Morgan says. “But they’re at a considerable amount of political risk” if patients have negative reactions to the SEBs.

Many biologic companies are positioning themselves to benefit either way by creating their own SEBs – Amgen, for example, produces a number of biologics and has begun creating a portfolio of biosimilars of their competitor’s products as well. “There’s only one or two biosimilars approved in Canada, and there’s a long list of biologic drugs available in Canada,” says Amgen’s Furlong. “All these drugs will come to the end of their patents, and when they do, the option of having a lower cost alternative is going to be captured by someone.”

Lessons from Europe and USA

The market for biosimilars goes beyond Canada’s borders. In the U.S., regulations around biologics were introduced as part of the Affordable Care Act. They should include a shortened development and approval program for SEBs, but final regulations aren’t yet in place. There aren’t any biosimilars currently on the market in the States; the first submission was filed last summer.

Europe, on the other hand, is well ahead of us. Fifteen biosimilars are marketed in Europe, five of which have been available since 2007. The European Medicines Agency’s overarching principle in its recently revised requirements is that biosimilars should be “highly similar to the reference medicinal product in physicochemical and biological terms.” For a protein, for example, the amino acid sequence would need to be the same. Individual countries decide if the drugs should be interchangeable.

“It was all a grand experiment when SEBs came out in Europe,” says Martinson. So what happened? The uptake hasn’t been huge – only 8% of the biologic market in the EU is spent on biosimilars. Their use varies immensely from country to country, from Britain, which encourages the use of brand name biologics due to safety concerns, to Germany, which is now a major biosimilar manufacturer and has created biosimilar prescribing quotas in some cities. Half of the biosimilars used in Europe are in France and Germany.

In Europe, biosimilars that are used long-term have been less popular than short-term ones, suggesting doctors may be more likely to prescribe biosimilars to patients who are biologically naive. A European Commission Consensus Paper from 2013 reads, “There is relatively little data available on the number of patients that have been switched between biopharmaceuticals in clinical practice.”

At this point, “policy approaches still vary dramatically,” says Morgan. “Everyone is trying to balance due caution with the goal of promoting price competition.”

Enter the debate: reply to an existing comment

8 comments

Joel LexchinJanuary 8th, 2015 at 11:07 pm

I agree that we need to be concerned about the effectiveness and safety of biosimilars. However, this same concern needs to be applied when the manufacturer of the original biologic changes the manufacturing process. As the commentary points out these are “complex molecules, and they can change in unpredictable ways during manufacturing.” Therefore, we equally need to be assured that changes in manufacturing don’t affect the safety and effectiveness of the original product. What processes are being put in place to deal with this situation?

Because of the complexity of biologic molecules as well as their production processes, the most important question is whether or not a biosimilar is truly essential equivalent in terms of clinical effectiveness and side effects. The challenge is to come up with protocols and standards to test biosimilars and to monitor the resulting impact on patients over time. As with any major advancement in healthcare technology, the patient population ultimately becomes participants in the “final” clinical trial of each new biosimilar introduced into our healthcare system.

“Drift” will be an important federal regulatory policy consideration with regards to interchangeability. Outside of interchangeability drift already occurs in products between countries, but this is generally not an issue for patients, as one wouldn’t receive a product in more than one country (switch between products). Personally, I think provincial decisions on interchangeability would take some time, possibly when enough clinical trial extension data is generated from patients who switch between Remicade and Inflectra/Remsima.

Something that wasn’t touched on – to my knowledge Health Canada hasn’t added a prefix or suffix to the international non proprietary name, where Remicade and Inflectra/Remsima are infliximab. It will be interesting to see how this affects pharmacovigilance programs, or a pharmacists interpretation of “infliximab”.

This is an important article and I thank the writers for it. I am trying to look at this issue as a physician, taxpayer and patient.

The statement by Steve Morgan, director of the Centre for Health Services and Policy Research at UBC, that “The dialogues around biosimilars sounds very familiar to the dialogue around generics in the 1970s. While it’s too early to declare SEBs and biologics interchangeable, the safety concerns are manageable,” concerns me very much.

The ramifications could be more serious for Subsequent Entry Biologics (SEB), but since I attended 2 lectures in the last year about equivalence of generic glaucoma medications to brand names as well as generics in general, I am very concerned. Although it is considered an accepted fact that generics work as well as the original branded drugs, apparently one of the original papers on which this fact is based appears to be a very weak study. I was flabbergasted and frightened to hear that the study had only a handful of drugs, and worse, an extremely low number of patients.

The following statement in the article is also concerning: “Like their generic counterparts, SEBs, which are approved by Health Canada on a drug-by-drug basis, require less proof of safety and efficacy than new biologics … clinical trials aren’t as important as they are for new drugs. That’s because SEBs are deemed similar enough to the original biologic for some of the information to be transferable.”

Another worrisome point from the article: “Britain, which encourages the use of brand name biologics due to safety concerns”

%featured%Differences between a generic drug and the brand name may not make a difference in most cases but unless there are clinical studies for each drug, we do not really know. %featured%There is even variability among the different generics themselves. Although outside my current scope of practice of medicine, I would think that small differences in bioequivalence are important in drugs like Digoxin, Coumadin and thyroid medication.

Generic drugs in ophthalmology have become an issue as many of our glaucoma drugs are now coming off patent. One example of this is the following article written by University of Toronto glaucoma specialist Dr. Graham Trope:

The conclusion is that , “American and Canadian Timoptic XE eye drops vary significantly from the generics in drop volume, viscosity, surface tension, and bottle tip. Canadian brand-name Timoptic delivered significantly smaller drop volumes than generic Apo-Timop. Careful consideration should be given to drop viscosity and bottle design when generic ophthalmic products are evaluated for interchangeability and market entry.”

When they were introduced, drugs of the same class had to do their own clinical trials. Regulations were not relaxed because of similarities to approved drugs. Did not each of the statins, SSRI’s and Cephalosporins require new clinical trials to prove their efficacy and safety? It appears that we will be doing the clinical trials after approving the SEB drugs.

“The solution that comes immediately to mind would be for bioequivalents to do their own clinical trials and then compete on price or even better effectiveness.” This will almost certainly raise the cost. As a physician, I am concerned about bioequivalence and patient safety. As a tax payer, I am concerned about cost. As a patient, I am concerned about bioequivalence, patient safety and cost.

This document is provided under the terms of a CreativeCommons Attribution Non-commercial Share Alike license. The terms of the license are available at: http://creativecommons.org/licenses/by-nc-sa/3.0/. Attributions are to be made to HealthyDebate.ca, a project under the direction of Dr. Andreas Laupacis, at the Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael’s Hospital.